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1.
Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551

RESUMO

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
2.
Hum Mol Genet ; 30(14): 1293-1304, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-33909047

RESUMO

Over 1200 variants in the ABCA4 gene cause a wide variety of retinal disease phenotypes, the best known of which is autosomal recessive Stargardt disease (STGD1). Disease-causing variation encompasses all mutation categories, from large copy number variants to very mild, hypomorphic missense variants. The most prevalent disease-causing ABCA4 variant, present in ~ 20% of cases of European descent, c.5882G > A p.(Gly1961Glu), has been a subject of controversy since its minor allele frequency (MAF) is as high as ~ 0.1 in certain populations, questioning its pathogenicity, especially in homozygous individuals. We sequenced the entire ~140Kb ABCA4 genomic locus in an extensive cohort of 644 bi-allelic, i.e. genetically confirmed, patients with ABCA4 disease and analyzed all variants in 140 compound heterozygous and 10 homozygous cases for the p.(Gly1961Glu) variant. A total of 23 patients in this cohort additionally harbored the deep intronic c.769-784C > T variant on the p.(Gly1961Glu) allele, which appears on a specific haplotype in ~ 15% of p.(Gly1961Glu) alleles. This haplotype was present in 5/7 of homozygous cases, where the p.(Gly1961Glu) was the only known pathogenic variant. Three cases had an exonic variant on the same allele with the p.(Gly1961Glu). Patients with the c.[769-784C > T;5882G > A] complex allele exhibit a more severe clinical phenotype, as seen in compound heterozygotes with some more frequent ABCA4 mutations, e.g. p.(Pro1380Leu). Our findings indicate that the c.769-784C > T variant is major cis-acting modifier of the p.(Gly1961Glu) allele. The absence of such additional allelic variation on most p.(Gly1961Glu) alleles largely explains the observed paucity of affected homozygotes in the population.

3.
JAMA Ophthalmol ; 139(6): 654-657, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33792637

RESUMO

Importance: Probing differences in disease prevalence between sexes is challenging, especially in mendelian diseases. Independent replication of any association study is warranted. Objective: To evaluate whether the recently reported association between sex and mild ABCA4 alleles among patients with autosomal recessive Stargardt disease (STGD1) is reproducible. Design, Setting, and Participants: Sequencing and clinical data from 644 unrelated patients with genetically confirmed STGD1 were analyzed in a cross-sectional study at the Department of Ophthalmology, Columbia University, New York, New York. Data were collected from June 1999 to October 2020. Main Outcomes and Measures: Sex, best-corrected visual acuity, and age at onset among patients with STGD1 with and without mild ABCA4 alleles. Results: A total of 644 patients with STGD1 with at least 2 pathogenic variants were included in the study. The mean (SD) age was 38.6 (17.2) years, and 352 participants (54.7%) were female. The proportion of women was slightly higher in the entire cohort and in most allele categories, although none of the differences were statistically significant. The proportion of women carrying the c.5603A>T p.(Asn1868Ile) allele was 7% (95% CI, -9 to 23) higher than in the subgroup not carrying any mild alleles (P = .32). The proportion of women carrying the c.5882G>A p.(Gly1961Glu) allele was 2% (95% CI, -12 to 15) higher than in the subgroup not carrying any mild alleles (P = .77). The difference between the total mild allele subcohort and the no mild allele subcohort was 3% (95% CI, -8 to 14; P = .48). Compared with patients in the no mild allele category, patients with mild alleles exhibited significantly delayed disease onset (mean [SD] age, 23.1 [11.6] for those with the c.5882G>A allele and 31.7 [13.5] years for those with the c.5603A>T allele vs 18.6 [11.8] years for those with no mild alleles; P < .001) and preserved visual acuity (5882G>A subgroup: mean [SD] logMAR, 0.65 [0.66]; 95% CI, 0.63-0.68; c.5603A>T subgroup: 0.64 [0.39]; 95% CI, 0.58-0.70; those with no mild alleles: 1.00 [0.57]; 95% CI, 0.96-1.03; P < .001). Conclusions and Relevance: This independent analysis of a larger cohort of individuals with Stargardt disease did not support the association between sex and certain mild ABCA4 alleles. While sex is undoubtedly an important variable in medicine, its putative association with clinical outcomes should be rigorously scrutinized.

4.
Leuk Res ; 103: 106539, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33647818

RESUMO

BACKGROUND: Acute leukemia with mixed-phenotype blasts is associated with poor outcomes. There are no standard treatment regimens. Due to disease heterogeneity, controversy exists over whether an AML-based, ALL-based, or a combined (hybrid) AML/ALL-based regimen is most appropriate. MATERIALS AND METHODS: We conducted a single-center, retrospective case series review of patients with acute leukemia with mixed phenotype blasts as described by the European Group for Immunological Characterization of Leukemia (EGIL) or the 2008 WHO classification. Patients were treated from November 2014 and December 2019 with the combination chemotherapy regimen FLAG-idarubicin-vincristine-prednisone with or without rituximab. Outcomes included induction response, time to transplant, time to relapse, overall survival, time to neutrophil or platelet recovery, infection, and duration of hospitalization. RESULTS: The median age was 68 years (range 21-77). Six patients (87.5 %) had unfavorable/complex cytogenetics. All patients achieved a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). Estimated 1-year overall survival was 85.7 %. There were no deaths during induction, with a 22 day median duration of hospitalization for induction. CONCLUSION: The combination of FLAG, idarubicin, vincristine, and prednisone (FLAG-VIPR) demonstrated favorable induction responses in a disease state with historically poor outcomes and should be studied in a prospective clinical trial.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Mieloide Aguda , Prednisona/administração & dosagem , Vidarabina/análogos & derivados , Vincristina/administração & dosagem , Adulto , Idoso , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Vidarabina/administração & dosagem
5.
Pathology ; 53(3): 400-407, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33642096

RESUMO

Advances in digital pathology have allowed a number of opportunities such as decision support using artificial intelligence (AI). The application of AI to digital pathology data shows promise as an aid for pathologists in the diagnosis of haematological disorders. AI-based applications have embraced benign haematology, diagnosing leukaemia and lymphoma, as well as ancillary testing modalities including flow cytometry. In this review, we highlight the progress made to date in machine learning applications in haematopathology, summarise important studies in this field, and highlight key limitations. We further present our outlook on the future direction and trends for AI to support diagnostic decisions in haematopathology.

6.
Retin Cases Brief Rep ; 15(2): 179-184, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30015775

RESUMO

PURPOSE: To describe the retinal findings in a 25-year-old white woman in whom a diagnosis of Boucher-Neuhäuser Syndrome (BNS) was supported by genetic testing, which identified a missense and novel nonsense mutation in the PNPLA6 gene. METHODS: Observational case report of a 25-year-old woman who presented with primary amenorrhea, cerebellar ataxia, and mild retinal pigmentary abnormalities. Neurologic, endocrine, and genetic evaluations established a diagnosis of BNS. RESULTS: Clinical examination and multimodal imaging documented focal outer retinal and retinal pigment epithelium changes including bilateral foveal stippling and a circular area of hypopigmentation in the superior macula of the left eye. Optical coherence tomography showed a linear area of outer retinal attenuation superonasal to the fovea and multiple foci of pinpoint outer retinal defects in the temporal macula of the left eye. Humphrey visual field 24-2 testing showed nonspecific defects in both eyes. Full-field electroretinography showed no evidence of a generalized retinal dysfunction. CONCLUSION: Recognition that the chorioretinal abnormalities occurring in BNS can be rather subtle is essential because the diagnosis of BNS may depend on their detection. To the best of our knowledge, this is the first report in the ophthalmic literature of mild chorioretinal changes in a patient with BNS testing positive for a mutation in the PNPLA6 gene.

7.
Acta Cytol ; 65(1): 105-110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32882689

RESUMO

Fine needle aspiration (FNA) has become increasingly popular in the evaluation of lymph nodes for lymphoproliferative disorders, but there are limitations to accurate subclassification of lymphoma using morphology alone. This case aims to expand diagnostic considerations of large B-cell populations identified on FNA material. We also address the significance of Epstein-Barr virus (EBV) DNA in the workup of patients with suspected lymphoma by FNA.


Assuntos
Linfócitos B/patologia , Linfonodos/patologia , Linfoma de Células B/diagnóstico , Linfoma de Células B/patologia , Idoso , Biópsia por Agulha Fina/métodos , Citodiagnóstico/métodos , Humanos , Masculino
8.
Clin Case Rep ; 8(11): 2286-2288, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33235778

RESUMO

The diagnosis of pure erythroid leukemia (PEL) can be challenging. Prompt identification of CD45+, CD34-, CD71+, CD117+, and E-cadherin+ erythroblasts is important. The differential diagnosis is broad and includes megaloblastic anemia.

9.
J Pathol Inform ; 11: 23, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042602

RESUMO

Digital displays (monitors) are an indispensable component of a pathologists' daily workflow, from writing reports, viewing whole-slide images, or browsing the Internet. Due to a paucity of literature and experience surrounding display use and standardization in pathology, the Food and Drug Administration's (FDA) has currently restricted FDA-cleared whole-slide imaging systems to a specific model of display for each system, which at this time consists of only medical-grade (MG) displays. Further, given that a pathologists' display will essentially become their new surrogate "microscope," it becomes exceedingly important that all pathologists have a basic understanding of fundamental display properties and their functional consequences. This review seeks to: (a) define and summarize the current and emerging display technology, terminology, features, and regulation as they pertain to pathologists and review the current literature on the impact of different display types (e.g. MG vs. consumer off the shelf vs. professional grade) on pathologists' diagnostic performance and (b) discuss the impact of the recent digital pathology device componentization and the coronavirus disease 2019 public emergency on the pixel pathway and display use for remote digital pathology. Display technology has changed dramatically over the past 20 years and continues to change at a rapid rate. There is a paucity of published studies to date that investigate how display type affects pathologist performance, with more research necessary in order to develop standards and minimum specifications for displays in digital pathology. Given the complexity of modern displays, pathologists must become better informed regarding display technology if they wish to have more choice over their future "microscopes."

10.
Invest Ophthalmol Vis Sci ; 61(11): 41, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32976563

RESUMO

Purpose: To increase our understanding of the mechanisms underlying hydroxychloroquine (HCQ) retinopathy, analyses by quantitative fundus autofluorescence (qAF) and near-infrared fundus autofluorescence (NIR-AF) were compared to results obtained by recommended screening tests. Methods: Thirty-one patients (28 females, 3 males) were evaluated with standard automated perimetry and spectral domain optical coherence tomography (SD-OCT); 28 also had multifocal electroretinography (mfERG). Measurement of short-wavelength fundus autofluorescence (SW-AF) by qAF involved the use of an internal fluorescent reference and intensity measurements in eight concentric segments at 7° to 9° eccentricity. For semiquantitative analysis of NIR-AF, intensities were acquired along a vertical axis through the fovea. Results: Four of 15 high-dose (total dose >1000 g, daily dose >5.0 mg/kg) patients and one of 16 low-dose (total dose <1000 g, daily dose 4.4 mg/kg) patients were diagnosed with HCQ-associated retinopathy based on abnormal 10-2 visual fields, SD-OCT, and SW-AF imaging. Three of the high-dose patients also had abnormal mfERG results. Of the five patients exhibiting retinopathy, two had qAF color-coded images revealing higher intensities inferior, nasal, and lateral to the fovea. The abnormal visual fields also exhibited superior-inferior differences. Mean NIR-AF gray-level intensities were increased in four high-dose patients with no evidence of retinopathy. In two patients with retinopathy, NIR-AF intensity within the parafovea was below the normal range. One high-dose patient (6.25 mg/kg) had only abnormal mfERG results. Conclusions: These findings indicate that screening for HCQ retinopathy should take into consideration superior-inferior differences in susceptibility to HCQ retinopathy.


Assuntos
Angiofluoresceinografia/métodos , Hidroxicloroquina/efeitos adversos , Doenças Retinianas/diagnóstico , Epitélio Pigmentado da Retina/patologia , Tomografia de Coerência Óptica/métodos , Campos Visuais/fisiologia , Adolescente , Adulto , Idoso , Antirreumáticos/efeitos adversos , Criança , Eletrorretinografia , Feminino , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/fisiopatologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Campos Visuais/efeitos dos fármacos , Adulto Jovem
11.
Eur J Ophthalmol ; : 1120672120957599, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32927963

RESUMO

INTRODUCTION: Mutations in the cone-rod homeobox (CRX) gene, a known cause of inherited retinal dystrophy, are characterized by extensive phenotypic heterogeneity. We describe a novel presentation of rod-cone dystrophy (RCD) phenocopying pigmented paravenous retinochoroidal atrophy associated with a mutation in CRX. CASE DESCRIPTION: A 53-year-old man and his 48-year-old brother presented with a history of progressive vision loss and nyctalopia. Fundus examination revealed a bull's eye lesion with chorioretinal atrophy and intraretinal pigment migration, while spectral-domain optical coherence tomography (SD-OCT) demonstrated retinal thinning with outer retinal atrophy. On short-wavelength autofluorescence (SW-AF) imaging, an atypical paravenous pattern of atrophy with a surrounding hyperautofluorescent border was observed. Full-field electroretinogram (ffERG) revealed a rod-cone pattern of dysfunction. A heterozygous pathogenic variant, c.119G>A:p.(Arg40Gln), in the CRX gene was identified in both brothers and segregated in their family. CONCLUSION: This case report broadens the currently known phenotypic presentations of CRX-associated retinopathy and suggests that mutations in CRX may be associated with pigmented paravenous retinochoroidal atrophy.

12.
Elife ; 92020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32936072

RESUMO

Notch signaling regulates squamous cell proliferation and differentiation and is frequently disrupted in squamous cell carcinomas, in which Notch is tumor suppressive. Here, we show that conditional activation of Notch in squamous cells activates a context-specific gene expression program through lineage-specific regulatory elements. Among direct Notch target genes are multiple DNA damage response genes, including IER5, which we show is required for Notch-induced differentiation of squamous carcinoma cells and TERT-immortalized keratinocytes. IER5 is epistatic to PPP2R2A, a gene that encodes the PP2A B55α subunit, which we show interacts with IER5 in cells and in purified systems. Thus, Notch and DNA-damage response pathways converge in squamous cells on common genes that promote differentiation, which may serve to eliminate damaged cells from the proliferative pool. We further propose that crosstalk involving Notch and PP2A enables tuning and integration of Notch signaling with other pathways that regulate squamous differentiation.


Assuntos
Diferenciação Celular/genética , Células Epiteliais/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Proteínas Nucleares/metabolismo , Receptores Notch/metabolismo , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular , Dano ao DNA/genética , Humanos , Proteínas Imediatamente Precoces/genética , Queratinócitos/metabolismo , Proteínas Nucleares/genética , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Receptores Notch/genética , Transdução de Sinais/genética
13.
Am J Ophthalmol ; 218: 40-53, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32445700

RESUMO

PURPOSE: To characterize the progression of optical gaps and expand the known etiologies of this phenotype. DESIGN: Retrospective cohort study. METHODS: Thirty-six patients were selected based on the identification of an optical gap on spectral-domain optical coherence tomography (OCT) from a large cohort of patients (N = 746) with confirmed diagnoses of inherited retinal dystrophy. The width and height of the gaps in 70 eyes of 36 patients were measured by 2 independent graders using the caliper tool on Heidelberg Explorer. Measurements of outer and central retinal thickness were also evaluated and correlated with gap dimensions. RESULTS: Longitudinal analysis confirmed the progressive nature of optical gaps in patients with Stargardt disease, achromatopsia, occult macular dystrophy, and cone dystrophies (P < .003). Larger changes in gap width were noted in patients with Stargardt disease (78.1 µm/year) and cone dystrophies (31.9 µm/year) compared with patients with achromatopsia (16.2 µm/year) and occult macular dystrophy (15.4 µm/year). Gap height decreased in patients with Stargardt disease (6.5 µm/year; P = .02) but increased in patients with achromatopsia (3.3 µm/year) and occult macular dystrophy (1.2 µm/year). Gap height correlated with measurements of central retinal thickness at the fovea (r = 0.782, P = .00012). Interocular discordance of the gap was observed in 7 patients. Finally, a review of all currently described etiologies of optical gap was summarized. CONCLUSION: The optical gap is a progressive phenotype seen in an increasing number of etiologies. This progressive nature suggests a use as a biomarker in the understanding of disease progression. Interocular discordance of the phenotype may be a feature of Stargardt disease and cone dystrophies.


Assuntos
Biomarcadores , Defeitos da Visão Cromática/diagnóstico por imagem , Distrofias de Cones e Bastonetes/diagnóstico por imagem , Degeneração Macular/diagnóstico por imagem , Retinite Pigmentosa/diagnóstico por imagem , Doença de Stargardt/diagnóstico por imagem , Tomografia de Coerência Óptica , Adolescente , Adulto , Idoso , Proteínas de Ligação ao Cálcio/genética , Criança , Defeitos da Visão Cromática/fisiopatologia , Distrofias de Cones e Bastonetes/fisiopatologia , Progressão da Doença , Eletrorretinografia , Feminino , Humanos , Degeneração Macular/fisiopatologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Fenótipo , Retina/fisiopatologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/fisiopatologia , Estudos Retrospectivos , Doença de Stargardt/fisiopatologia , Acuidade Visual/fisiologia , Proteínas rab de Ligação ao GTP/genética
14.
Artigo em Inglês | MEDLINE | ID: mdl-32238402

RESUMO

We report the diagnostic challenges and the clinical course of a patient with an extraordinary presentation of B-lymphoblastic leukemia (B-ALL) with eosinophilia. We identified a novel ZBTB20-JAK2 gene fusion as a chimeric RNA transcript using the Archer platform. This gene fusion from the same patient was recently identified by Peterson et al. (2019) at the genomic level using a different sequencing technology platform. The configuration of this gene fusion predicts the production of a kinase-activating JAK2 fusion protein, which would normally lead to a diagnosis of Philadelphia chromosome-like B-ALL (Ph-like B-ALL). However, the unusual presentation of eosinophilia led us to demonstrate the presence of this gene fusion in nonlymphoid hematopoietic cells by fluorescence in situ hybridization (FISH) studies with morphologic correlation. Therefore, we believe this disease, in fact, represents blast crisis arising from an underlying myeloid neoplasm with JAK2 rearrangements. This case illustrates the difficulty in differentiating Ph-like B-ALL and myeloid/lymphoid neoplasm with eosinophilia and gene rearrangements (MLN-EGR) in blast crisis. As currently defined, the diagnosis of MLN-EGR relies on the hematologic presentations and the identification of marker gene fusions (including PCM1-JAK2, ETV6-JAK2, and BCR-JAK2). However, these same gene fusions, when limited to B-lymphoblasts, also define Ph-like B-ALL. Yet, our case does not conform to either condition. Therefore, the assessment for lineage restriction of gene rearrangements to reflect the pathophysiologic difference between B-ALL and MLN-EGR in blast crisis is likely a more robust diagnostic approach and allows the inclusion of MLN-EGR with novel gene fusions.


Assuntos
Janus Quinase 2/genética , Leucemia/diagnóstico , Leucemia/genética , Proteínas do Tecido Nervoso/genética , Proteínas de Fusão Oncogênica/genética , Fenótipo , Fatores de Transcrição/genética , Adulto , Biópsia , Medula Óssea/patologia , Terapia Combinada , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Síndrome Hipereosinofílica/diagnóstico , Síndrome Hipereosinofílica/genética , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia/terapia , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Terapêutica
15.
Invest Ophthalmol Vis Sci ; 61(4): 13, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32298433

RESUMO

Purpose: To analyze the progression of choriocapillaris (CC) impairment in recessive Stargardt disease (STGD) and compare it to the progression of retinal pigment epithelium (RPE) atrophy. Methods: Fifty-five patients with a clinical diagnosis of STGD and genetic confirmation of pathogenic biallelic variants in ABCA4 were imaged with short-wavelength fundus autofluorescence (SW-AF) and optical coherence tomography angiography (OCTA) at a single clinic visit, whereas a subset of 12 patients were imaged with the same modalities at two different clinic visits. Results: We observed three stages of CC impairment: an area of bright yet intact macular CC (11 patients), regions of vascular rarefaction and incomplete CC atrophy within an area of bright CC (10 patients), and areas of extensive CC atrophy (26 patients). These changes correlated to the degree of RPE atrophy observed in SW-AF imaging. Furthermore, 8 patients presented with early changes on SW-AF, but healthy CC. Quantitative analyses of the atrophic changes revealed that the area of RPE atrophy is larger (9.6 ± 1.7 mm2 vs. 6.9 ± 1.3 mm2, P < 0.001) and that it progresses at a faster rate (1.1 ± 0.1 mm2/year vs. 0.8 ± 0.2 mm2/year, P = 0.004) than the corresponding area of CC atrophy. Conclusions: CC impairment is progressive and OCTA imaging can be used to demonstrate the stages, which culminate in extensive CC atrophy. Furthermore, CC impairment is secondary to RPE atrophy in STGD. We further advocate the use of SW-AF and OCTA imaging in monitoring the progression of STGD.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Corioide/patologia , Epitélio Pigmentado da Retina/patologia , Doença de Stargardt/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrofia , Criança , Progressão da Doença , Feminino , Angiofluoresceinografia , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Óptica , Estudos Retrospectivos , Doença de Stargardt/genética , Tomografia de Coerência Óptica , Adulto Jovem
16.
Prog Retin Eye Res ; 79: 100861, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32278709

RESUMO

The ABCA4 protein (then called a "rim protein") was first identified in 1978 in the rims and incisures of rod photoreceptors. The corresponding gene, ABCA4, was cloned in 1997, and variants were identified as the cause of autosomal recessive Stargardt disease (STGD1). Over the next two decades, variation in ABCA4 has been attributed to phenotypes other than the classically defined STGD1 or fundus flavimaculatus, ranging from early onset and fast progressing cone-rod dystrophy and retinitis pigmentosa-like phenotypes to very late onset cases of mostly mild disease sometimes resembling, and confused with, age-related macular degeneration. Similarly, analysis of the ABCA4 locus uncovered a trove of genetic information, including >1200 disease-causing mutations of varying severity, and of all types - missense, nonsense, small deletions/insertions, and splicing affecting variants, of which many are located deep-intronic. Altogether, this has greatly expanded our understanding of complexity not only of the diseases caused by ABCA4 mutations, but of all Mendelian diseases in general. This review provides an in depth assessment of the cumulative knowledge of ABCA4-associated retinopathy - clinical manifestations, genetic complexity, pathophysiology as well as current and proposed therapeutic approaches.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , DNA/genética , Terapia Genética/métodos , Mutação , Doenças Retinianas/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Humanos , Fenótipo , Doenças Retinianas/metabolismo , Doenças Retinianas/terapia
17.
Ophthalmic Genet ; 40(4): 369-375, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31576780

RESUMO

Background: The extensive phenotypic heterogeneity of monogenic diseases can be largely traced to intragenic variation; however, recent advances in clinical detection and gene sequencing have uncovered the emerging role of non-allelic variation (i.e. genetic trans-modifiers) in shaping disease phenotypes. Identifying these associations are not only of significant diagnostic value, but also provides scientific insight into the expanded molecular etiology of rare diseases. This reports describes the discordant clinical manifestation of a family segregating mutations in ABCA4 and PROM1. Methods: Three patients across a two generation family underwent multimodal imaging and functional testing of the retina including color photography, fundus autofluorescence (AF), spectral domain-optical coherence tomography (SD-OCT) and full-field electroretinography (ffERG). Genetic characterization was carried out by direct Sanger and whole exome sequencing. Results: Clinical examination revealed similar retinal degenerative phenotypes in the proband and her mother. Despite being younger, the proband's phenotype was more advanced and exhibited additional features related to Stargardt disease not found in the mother. Whole exome sequencing identified a pathogenic missense variant in PROM1, c.400C > T, p.(Arg134Cys), as the underlying cause of retinal disease in both the proband and mother. Sequencing of the ABCA4 locus uncovered a single disease-causing variant, c.5714 + 5G > A in the daughter segregating from the father who, surprisingly, also exhibited very subtle disease changes associated with STGD1 despite being a heterozygous carrier. Conclusions: Harboring an additional heterozygous ABCA4 mutation increases severity and confers STGD1-like features in patients with PROM1 disease which provides supporting evidence for their shared pathophysiology and potential treatment prospects.


Assuntos
Antígeno AC133/genética , Transportadores de Cassetes de Ligação de ATP/genética , Degeneração Macular/patologia , Mutação , Degeneração Retiniana/patologia , Doença de Stargardt/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Degeneração Macular/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Prognóstico , Degeneração Retiniana/genética , Doença de Stargardt/genética , Adulto Jovem
18.
Invest Ophthalmol Vis Sci ; 60(12): 3752-3761, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31499530

RESUMO

Purpose: To ascertain cellular constituents within islands of preserved retina in choroideremia (CHM) by multimodal imaging. Methods: CHM probands (16) and female carriers (9) of CHM were studied. Near-infrared autofluorescence (NIR-AF; 787-nm excitation; emission, >830 nm), short-wavelength autofluorescence (SW-AF; 488-nm excitation, 500- to 680-nm emission), and spectral-domain optical coherence tomography (SD-OCT) images were acquired with a confocal scanning laser ophthalmoscope. SW-AF intensities were measured by quantitative fundus autofluorescence (qAF), and NIR-AF intensity profiles were analyzed. Retinal thicknesses and visual acuity were measured. Results: In 19 of 31 eyes of affected males, islands of preserved NIR-AF signal were also visible as fluorescence signal in SW-AF images. Notable in 12 eyes were areas of speckled SW-AF that was hypoautofluorescent in the NIR-AF image. Islands of preserved NIR-AF and SW-AF signal were often associated with the presence of visible but thinned outer nuclear layer and discontinuous interdigitation zone, ellipsoid zone, and external limiting membrane. NIR-AF profiles revealed that even in areas of preserved retina, the NIR-AF signal from retinal pigment epithelium (RPE) melanin is greatly reduced. qAF was reduced overall. The fundus of carriers was characterized by a mosaicism in which patches of reduced NIR-AF colocalized with reduced SW-AF. Conclusions: In CHM-affected males, the presence of RPE was indicated by an NIR-AF signal and the absence of hypertransmission of OCT signal into the choroid. RPE preservation was associated with better visual acuity. In carriers, patches of reduced SW-AF colocalized with decreased NIR-AF and qAF was severely reduced.


Assuntos
Coroideremia/patologia , Epitélio Pigmentado da Retina/patologia , Adolescente , Adulto , Idoso , Criança , Coroideremia/diagnóstico por imagem , Coroideremia/genética , Feminino , Fundo de Olho , Heterozigoto , Humanos , Raios Infravermelhos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Imagem Óptica , Retina/patologia , Epitélio Pigmentado da Retina/diagnóstico por imagem , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia
19.
Sci Rep ; 9(1): 6436, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015497

RESUMO

Fundus autofluorescence (FAF) imaging is crucial to the diagnosis and monitoring of recessive Stargardt disease (STGD1). In a retrospective cohort study of 34 patients, we compared FAF imaging platforms varying in field size (30° and 55°: blue/SW-AF and NIR-AF; 200°: ultrawide-field, UWF-AF), excitation wavelength (488 nm, blue/SW-AF; 532 nm, UWF-AF and 787 nm, NIR-AF) and image processing. Due to reduced absorption of 532 nm and 787 nm light by macular pigment, foveal sparing was more readily demonstrable by green/UWF-AF and NIR-AF imaging. Prominent in green/UWF-AF images is a central zone of relatively elevated AF that is continuous inferonasal with a demarcation line bordering lower AF nasally and higher AF temporally. This zone and border are more visible in STGD1 than in healthy eyes and more visible with green/UWF-AF. With the development of AF flecks, inferonasal retina is initially spared. Central atrophic areas were larger in NIR-AF images than in blue/SW-AF and green/UWF-AF images and the presence of a contiguous hyperAF ring varied with imaging modality. Flecks visible as hyperAF foci in blue/SW-AF images were also visible in green/UWF-AF but were often hypoAF in NIR-AF. Since disease in STGD1 often extends beyond the 30° and 55° fields, green/UWF-AF has advantages including for pediatric patients. The imaging platforms examined provided complementary information.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Fóvea Central/diagnóstico por imagem , Imagem Óptica/métodos , Epitélio Pigmentado da Retina/diagnóstico por imagem , Doença de Stargardt/diagnóstico por imagem , Doença de Stargardt/genética , Transportadores de Cassetes de Ligação de ATP/deficiência , Adolescente , Adulto , Idoso , Criança , Feminino , Fóvea Central/metabolismo , Fóvea Central/patologia , Fundo de Olho , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Estudos Retrospectivos , Doença de Stargardt/metabolismo , Doença de Stargardt/patologia
20.
Cell Mol Life Sci ; 76(18): 3657-3665, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30976840

RESUMO

D190N, a missense mutation in rhodopsin, causes photoreceptor degeneration in patients with autosomal dominant retinitis pigmentosa (adRP). Two competing hypotheses have been developed to explain why D190N rod photoreceptors degenerate: (a) defective rhodopsin trafficking prevents proteins from correctly exiting the endoplasmic reticulum, leading to their accumulation, with deleterious effects or (b) elevated mutant rhodopsin expression and unabated signaling causes excitotoxicity. A knock-in D190N mouse model was engineered to delineate the mechanism of pathogenesis. Wild type (wt) and mutant rhodopsin appeared correctly localized in rod outer segments of D190N heterozygotes. Moreover, the rhodopsin glycosylation state in the mutants appeared similar to that in wt mice. Thus, it seems plausible that the injurious effect of the heterozygous mutation is not related to mistrafficking of the protein, but rather from constitutive rhodopsin activity and a greater propensity for chromophore isomerization even in the absence of light.


Assuntos
Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Retinite Pigmentosa/patologia , Rodopsina/genética , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Eletrorretinografia , Técnicas de Introdução de Genes , Glicosilação , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Estrutura Terciária de Proteína , Retina/metabolismo , Retina/patologia , Retinite Pigmentosa/metabolismo , Rodopsina/química , Rodopsina/metabolismo , Alinhamento de Sequência
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